In the United States, many hip fractures occur each year, causing significant disability and premature deaths. Cases of hip fractures cost an estimated $7 billion annually. Several etiologic factors are implicated in fracture risk including hormonal, metabolic, and genetic contributions. We propose to examine promising hormonal and genetic markers for hip fracture risk; this is a major objective of the Women's Health Initiative Observation Study (WHI-OS), a prospective study of over 93,000 postmenopausal women. Among WHI-OS participants, we will investigate whether low levels (especially very low levels) of estradiol, high levels of steroid hormone binding globulin, and low levels of insulin like growth factor 1 increase the risk of hip fracture. Recent studies also have identified promising polymorphisms in several candidate genes related to bone metabolism that may substantially affect hip fracture risk. We will test whether candidate polymorphisms in the following genes contribute to hip fracture risk: APOE, estrogen receptor alpha-l, transforming growth factor-beta and collagen type 1 alpha 1, and LDL receptor-related protein 5. Recent data support the functional role of these polymorphisms in the maintenance of bone mass and metabolism, suggesting that they may contribute to osteoporotic fracture risk. Identifying such hormonal and genetic markers for increased fracture risk ultimately may provide insight into treatment methods, at risk populations that could benefit from preventive measures, and new hypotheses about the pathophysiologic mechanisms for increased fracture risk. Among eligible WHI-OS participants aged 55-79 years at baseline, we will use a nested case-control study design to identify 400 cases of first hip fracture and 400 age-, ethnicity-, and center-matched controls for this study. This study will use previously collected baseline data and stored specimens in WHI-OS, including existing baseline serum and buffy coat samples and documentation/adjudication of hip fracture events. WHl data include comprehensive measurements of potential confounders and effect modifiers that will be considered in the analyses. The proposed study is a very efficient approach to understanding the etiologies of hip fracture.